GABAergic Mechanisms of Comorbid Alcohol and Nicotine Dependence

描述（由申请人提供）：酒精依赖和吸烟是高度相关的，然而检查潜在神经化学的研究很少。在人类中，吸烟似乎在酒精依赖恢复期间调节GABAA- BZR的可用性。临床数据表明，急性戒断期间酒精依赖非吸烟者GABAA-BZR可用性增加，而酒精依赖吸烟者则受到抑制。此外，在长时间戒酒期间，GABAA-BZR的可用性似乎有所下降；然而，这还没有得到系统的研究。本项目的目的是利用[123I]iomazenil和单光子发射计算机断层扫描（SPECT）来确定慢性口服给药乙醇的戒断与慢性乙醇和尼古丁联合给药对大脑GABAA- BZR的影响。我们还将研究同时戒除乙醇和尼古丁时GABAA-BZR可用性的变化，与持续暴露于尼古丁的情况下戒除乙醇时GABAA-BZR可用性的变化，以模拟同时戒酒和戒烟同时继续吸烟的人GABAA-BZR的变化。我们将获得50只青春期动物的扫描结果（每组n=10）。所有动物将在基线接受2次扫描，例如测试-重新测试。第一组自行服用慢性乙醇24周，并在停药1天、8天和12周时拍照。第二组自行服用慢性尼古丁24周，并在停药1天、8天和12周时进行影像学检查。3A组自行服用乙醇加尼古丁24周，并在1天、8天和12周时分别停止使用乙醇和尼古丁进行扫描。3B组将自行给药乙醇加尼古丁24周，并在停药1天、8天和12周时进行成像，但在停药期间将继续自行给药尼古丁。对照组4自行服用糖精24周，停用糖精后第1天、第8天和第12周成像。将获得核磁共振扫描以跟踪脑灰质、白质和脑脊液（CSF）的变化。我们假设：1)与基线和对照组相比，急性乙醇戒断期间GABAA-BZR的可用性增加，与基线和对照组相比，在乙醇戒断12周时GABAA-BZR的可用性降低；2)与基线或对照组相比，戒断期间GABAA-BZR可用性无变化；(3)与单独使用乙醇相比，乙醇和尼古丁联合使用会导致GABAA-BZR的可用性降低，即尼古丁会抑制乙醇诱导的GABAA-BZR的增加，而与同时使用乙醇和尼古丁相比，退出乙醇后尼古丁对GABAA-BZR可用性增加的抑制更大。这项研究的发现将促进对酒精和尼古丁依赖高共病的神经化学机制的理解，并将对治疗吸烟者和非吸烟者的酒精依赖有直接的临床意义。公共卫生相关性：拟议的实验将通过描绘GABAA-苯二氮卓类受体的大脑机制直接影响公众健康，GABAA-苯二氮卓类受体参与酒精依赖的恢复以及酒精依赖与吸烟的相互作用。这些研究将检查酒精和尼古丁的戒断，以确定这些药物对大脑化学的相互作用。这些研究最终将为如何更成功地治疗这些昂贵的成瘾提供信息。

DESCRIPTION (provided by applicant): Alcohol dependence and tobacco smoking are highly associated, yet studies examining the underlying neurochemistry are scarce. In humans, tobacco smoking appears to regulate the availability of the GABAA- BZR during the recovery from alcohol dependence. Clinical data suggest increased GABAA-BZR availability in alcohol dependent nonsmokers during acute withdrawal that is suppressed in alcohol dependent smokers. Additionally, there appears to be decreased GABAA-BZR availability during prolonged alcohol withdrawal; yet this has not been systematically studied. The purpose of this project is to determine the effects of withdrawal from chronic orally-delivered ethanol versus chronic co-administration of ethanol and nicotine on the GABAA- BZR in brain over time using [123I]iomazenil and single photon emission computed tomography (SPECT). We will also examine changes in GABAA-BZR availability during withdrawal from both ethanol and nicotine simultaneously, versus withdrawal from ethanol in the presence of continued nicotine exposure to model changes in GABAA-BZR in humans that quit drinking and smoking simultaneously vs. quitting drinking while continuing to smoke. We will obtain scans in 50 adolescent animals (n=10 per group). All animals will receive 2 scans at baseline, e.g., test-retest. Group 1 will self-administer chronic ethanol for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 2 will self-administer chronic nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 3A will self-administer ethanol plus nicotine for 24 weeks and will be scanned at 1 day, 8 days and 12 weeks withdrawal from both ethanol and nicotine. Group 3B will self-administer ethanol plus nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal from ethanol, but will continue to self-administer nicotine during this withdrawal period. Group 4, a control condition, will self-administer saccharin for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks after termination of saccharin. MRI scans will be obtained to track changes in brain gray and white matter and cerebrospinal fluid (CSF). We hypothesize that there will be 1) increased GABAA-BZR availability compared to baseline and controls during acute ethanol withdrawal and decreased GABAA-BZR availability compared to baseline and controls at 12 weeks ethanol withdrawal; 2) no change in GABAA-BZR availability compared to baseline or controls during nicotine withdrawal; and, 3) the combination of ethanol and nicotine will result in decreased GABAA-BZR availability compared to ethanol alone, i.e., nicotine will suppress the ethanol-induced increase, and withdrawal from ethanol into the presence of nicotine will result in a greater suppression of increased GABAA-BZR availability compared to withdrawal from ethanol and nicotine simultaneously. The findings from this study will advance the understanding of the neurochemical mechanisms that underlie the high comorbidity of alcohol and nicotine dependence and will have direct clinical implications for the treatment of alcohol dependence in both smokers and nonsmokers. PUBLIC HEALTH RELEVANCE: The proposed experiments will directly impact public health by delineating a brain mechanism, the GABAA- benzodiazepine receptor, which is involved in the recovery from alcohol dependence and in the interaction of alcohol dependence and tobacco smoking. These studies will examine the withdrawal from both alcohol and nicotine to determine the interaction of these drugs on brain chemistry. These studies will ultimately provide information on how to more successfully treat these costly addictions.